Trigeminal Mechanisms of Oral Irritation

这项提案的总体目标是调查食品、饮料和其他消费品中常见刺激性化学物质产生口腔刺激的神经机制。一种多学科的实验方法将解决这一假设，即啮齿动物模型中三叉神经疼痛通路中的神经元以与人类感知相关的方式发出口腔刺激信号。具体目标如下。具体目的1.研究不同刺激性化学物质在人体内诱发感觉的不同模式。反复或持续口服某些刺激物(辣椒素、浓缩氯化钠)会引起刺激性，并逐渐增加强度(敏化)，而其他刺激物(尼古丁、薄荷醇)引起的刺激性下降(脱敏)。我们将研究其他刺激性化学物质(酸、芥子油、二氧化碳)是否可被归类为致敏或减敏。我们还将研究刺激物之间的相互作用(例如，交叉脱敏)，以及人类是否能够定性地区分刺激物，而不依赖于味觉或嗅觉线索。具体目的2.通过记录大鼠尾侧亚核(Vc)单个伤害性神经元对刺激性化学物质舌下刺激的反应，探讨口腔刺激的神经机制。我们将确定刺激诱发的VC神经元的放电模式是否与人类感觉分级的模式相关。辣椒素和其他敏感剂预计会导致放电的渐进性增加，而尼古丁和其他脱敏剂的放电预计会逐渐减少。另外的目标是测试“化学选择性”的VC神经元是否存在，以及VC中的中间神经元和上升投射神经元是否具有相似或不同的特性。具体目的3.通过确定化学刺激感觉或VC神经元的激活是否被特定的拮抗剂减少来研究信号转导机制。我们将集中于神经元烟碱受体、阿米洛利敏感离子通道、香草素(VR-1)受体和Na-/H-膜交换泵。用单单位记录法和c-FOG免疫组织化学方法检测Vc活性。具体目的4.建立口腔刺激的啮齿动物模型，使用配对偏好范式来测量水的消耗量与辣椒素的水溶液的消耗量。我们假设可检测到的辣椒素浓度将被拒绝。这个模型将被用来研究神经肽P物质在口腔刺激中的作用。具体目的5.使用敏感的两种选择强迫选择范式，检验口腔内刺激物降低人类对味道质量强度的判断的假设。在一项相应的动物研究中，我们将确定口服辣椒素是否会降低孤束核(NTS)神经元的反应。

The overall goal of this proposal is to investigate the neural mechanisms underlying oral irritation produced by common irritant chemicals in foods, beverages and other consumer products. A multidisciplinary experimental approach will address the hypothesis that neurons in the trigeminal pain pathway in a rodent model signal oral irritation in a manner that correlates with human perception. Specific aims are as follows. Specific Aim 1. To investigate the distinct patterns of sensation elicited by different irritant chemicals in human subjects. Repetitive or continual intraoral application of certain irritants (capsaicin, concentrated NaC1) elicits irritation that progressively increases in intensity (sensitization), while irritation elicited by other irritants (nicotine menthol) declines (desensitization). We will study if additional irritant chemicals (acids, mustard oil, CO2) can be categorized as sensitizing or desensitizing. We will also investigate interactions between irritants (e.g., cross-desensitization), and if humans can qualitatively discriminate between irritants independent of taste or smell cues. Specific Aim 2. To investigate neural mechanisms of oral irritation, by recording responses of single nociceptive neurons in subnucleus caudalis (Vc) to lingual application of irritant chemicals in rats. We will determine if the irritant-evoked Vc neuronal firing pattern correlates with the pattern of human sensory ratings. Capsaicin and other sensitizing agents are predicted to elicit a progressive increase in firing, while a progressive decline in firing is predicted for nicotine and other desensitizing agents. Additional goals are to test if "chemo- selective" Vc neurons exist, and if interneurons and ascending projection neurons in Vc have similar or different properties. Specific Aim 3. To investigate transduction mechanisms, by determining if chemically-evoked irritant sensation, or activation of Vc neurons, is reduced by specific antagonists. We will focus on neuronal nicotinic receptors, amiloride-sensitive ion channels, vanilloid (VR-1) receptors, and the Na-/H- membrane exchange pump. Vc activity will be measured by single-unit recording and by c-fog immunohistochemistry. Specific Aim 4. To develop a rodent model of oral irritation, using a paired preference paradigm to measure consumption of water vs. an aqueous solution of capsaicin. We hypothesize that detectable concentrations of capsaicin will be rejected. This model will be used to investigate the role of the neuropeptide, substance P, in oral irritation. Specific Aim 5. To test the hypothesis that intraoral irritants reduce human judgments of the intensity of taste qualities using a sensitive 2-alternative forced-choice paradigm. In a corresponding animal study, we will determine if responses of neurons in the n. tractus solitarius (NTS), a taste relay, are reduced by intraoral capsaicin.